Numerous chronic debilitating diseases of the skeletal system in vertebrates, including arthritis and related arthritic disorders, feature degradation of specialized avascular cartilaginous tissue known as articular cartilage that contains dedicated cartilage-producing cells, the articular chondrocytes. As described in greater detail below, articular chondrocytes, unlike other chondrocytes such as epiphyseal growth plate chondrocytes present at the ends of developing long bones (e.g., endochondral or costochondral chondrocytes), reside in and maintain joint cartilage having no vasculature. Thus lacking a blood supply as an oxygen source, articular chondrocytes are believed to generate metabolic energy, for example bioenergetic ATP production, predominantly by anaerobic (e.g., glycolytic) respiration, and not from aerobic mitochondrial oxidative phosphorylation (Stefanovich-Racic et al., 1994 J. Cell Physiol. 159:274–280). Because even under aerobic conditions, articular chondrocytes may consume little oxygen and thus appear to differ from a wide variety of vertebrate cell types (Stefanoviceh-Racic et al., 1994), mitochondrial roles in arthritic disorders have been largely ignored.
I. Structure and Function of Musculoskeletal Joints
Evolution has developed extraordinarily efficient musculoskeletal systems for generating and controlling motion in vertebrates such as mammals, reptiles, birds and fish. The musculoskeletal system thus efficiently delivers useful mechanical energy and load support, but is also capable of synthesizing, processing and organizing complex macromolecules to fashion tissues and organs specialized to perform specific mechanical functions. The joints are an important subset of the specialized structures of the musculoskeletal system, and many distinct types of joints exist in the body. Freely moving joints (e.g., ankle, elbow, hip, knee, shoulder, and joints of the fingers, toes and wrist) are known as diarthrodial or synovial joints. In contrast, the intervertebral joints of the spine are not diarthrodial joints as they are fibrous and do not move freely, although they do provide the flexibility required by the spine.
Diarthrodial joints have some common structural features. First, all diarthrodial joints are enclosed in a strong fibrous capsule. Second, the inner surfaces of the joint capsule are lined with a metabolically active tissue, the synovium, which secretes the synovial fluid that lubricates the joint and provides the nutrients required by the avascular cartilage. Third, the articulating bone ends in the joint are lined with a thin layer of hydrated soft tissue known as articular cartilage. Fourth, the joint is stabilized by, and its range of motion controlled by, ligaments and tendons that may be inside or outside the joint capsule.
The surface linings of diarthrodial joints, i.e., the synovium and articular cartilage layers, form the joint cavity that contains the synovial fluid. Thus, in vertebrate skeletal joints, the synovial fluid, articular cartilage, and the supporting bone form a smooth, nearly frictionless bearing system. While diarthrodial joints are subjected to an enormous and varied range of load conditions, the cartilage surfaces undergo little wear and tear (e.g., structural degradation) under normal circumstances. Indeed, most human joints are capable of functioning effectively under very high loads and stresses and at very low operating speeds. These performance characteristics demand efficient lubrication processes to minimize friction and wear of cartilage in the joint. Severe breakdown of the joint cartilage by biochemical and/or biomechanical processes leads to arthritis, which is therefore generally defined as a failure of the vertebrate weight bearing system.
Hyaline cartilage, as its name implies, is glass-smooth, glistening and bluish white in appearance, although older or diseased tissue tends to lose this appearance. The most common hyaline cartilage, and the most studied, is the articular cartilage, which covers the articulating surfaces of long boned and siesamoid bones within diarthrodial joints. As described above, articular cartilage consists of specialized cartilage cells known as articular chondrocytes, and a cartilaginous extracellular matrix comprised largely of two major classes of macromolecules, collagen and proteoglycans. Articular chondrocytes synthesize, deposit and reside in the three-dimensional extracellular matrix, and also synthesize some of the solutes and enzymes present in synovial fluid, which bathes the articular cartilage. Healthy articular cartilage forms a smooth surface between articulating bone ends to reduce the friction caused by movement. The synovial fluid further reduces this friction.
During the development of cartilage (chondrogenesis), chondroblasts derived from mesenchymal cells become trapped in small cavities or depressions known as lacunae, where they develop into articular chondrocytes which, in contrast to chondroblasts, have a limited capacity to replicate. Articular chondrocytes, however, mediate the synthesis, assembly, degradation and turnover of the macromolecules which comprise the cartilage extracellular matrix (ECM or simply “matrix”). Mechanochemical properties of this matrix contribute significantly to the biomechanical function of cartilage in vivo. Because the articular cartilage is not a vascularized tissue, articular chondrocytes are believed to reside in an environment of low oxygen tension and may therefore appear to preferentially derive metabolic energy by anaerobic (e.g., glycolytic) ATP biosynthesis (Stefanovich-Racic et al., 1994).
The structural integrity of articular cartilage is the foundation of optimal functioning of the skeletal joints, such as those found in the vertebrate hip, shoulders, elbows, hocks and stifles. Impaired skeletal joint function dramatically reduces an individual subject's mobility, such as that involved in rising from a sitting position or in climbing and descending stairs. As noted above, in order to maintain the structural and functional integrity of articular cartilage, articular chondrocytes constantly synthesize collagen and proteoglycans, the major components of the articular cartilage; chondrocytes also secrete the friction-reducing synovial fluid. This constant elaboration by articular chondrocytes of cartilage ECM macromolecules and synovial fluid provides the articular cartilage with a repair mechanism for most mechanical wear that may be caused by friction between the bone ends. However, such steady biosynthesis of cartilage components generates a constant demand for the precursors, or building blocks, of these macromolecules and synovial fluid components. Lack of these precursors will lead to defects in the structure and function of the skeletal joints. This deficiency occurs often when activity levels are very high, or when cartilage tissue is traumatized.
The menisci of the knee, and other similar structures such as the disc of the temporomandibular joint and the labrum of the shoulder, are specialized fibrocartilagenous structures that are vital for normal joint function. They are known to assist articular cartilage in distributing loads across the joint, to aid ligaments and tendons in stabilizing joints and to play a major role in shock absorption, and may further assist in lubricating the joint. Damage to these structures can lead to impaired joint function and to articular cartilage degeneration. Surgical removal of these fibrocartilagenous structures, for example, following apparently irreparable cartilage tears, can result in early onset of osteoarthritis. The menisci, disc and labrum are hydrated fibrocartilage structures composed primarily of type II collagen, with smaller amounts of other collagens and proteoglycans (including aggrecan and the smaller, non-aggregating proteoglycans) also present. These fibrocartilaginous structures contain a sparse population of resident cells that, like the articular chondrocytes of cartilage, are responsible for the synthesis and maintenance of this extracellular matrix.
II. Arthritic Disorders
Diarthrodial joints enable common bodily motions including limb movements associated with motor (e.g., ambulatory) functions and other activities of daily life. These joints typically perform their functions so well and efficiently that their existence may be innocuous until injury strikes or arthritis develops. From an engineering point of view, these natural biomechanical bearings are very uncommon structures. Healthy joints may function in a virtually frictionless and wear-resistant manner throughout all or most of a lifetime. Failure of the joint bearings surfaces (i.e., articular cartilage), as with mechanically engineered artificial bearings, means a failure of these bearings to provide their central functions, such as delivery of mechanical energy and load support.
In biomedical terms, failure of diarthrodial joints leads to arthritic disorders, the most common forms being osteoarthritis or degenerative joint disease, or chondrocalcinosis. Other forms of arthritic disorders include but are not limited to rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis, lupus erythematosous, gout and infectious arthritides (see, e.g., Gilliland et al., “Disorders of the joints and connective tissue,” Section 14, in Harrison's Principles of Internal Medicine, Eighth Ed., Thorn et al., eds. McGraw-Hill, New York, N.Y., 1977, pp. 2048–2080). Arthritic disorders can also include, or may result from, physical trauma (for example, acute physical injury that damages joint tissue, or repetitive motion syndrome) or dietary conditions (e.g., ricketts or other dietary deficiency diseases) that result in joint injury.
By far, the most prevalent arthritic disorders are rheumatoid arthritis (RA) and osteoarthritis (OA). RA, thought to be an autoimmune disorder, results in part from inflammation of the synovial membrane. In humans, peak onset of this disorder occurs in adults over 30 years of age (typically in their thirties and forties) and afflicts women three times more often than men. In extreme cases, chronic inflammation erodes and distorts the joint surfaces and connective tissue, resulting in severe articular deformity and constant pain. Moreover, RA often leads to OA, further compounding the destruction of the joint. The most common arthritic disorder, OA, is characterized by degenerative changes in the surface of the articular cartilage. Alterations in the physicochemical structure of the cartilage make it less resistant to compressive and tensile forces. Finally, complete erosion occurs, leaving the subchondral bone exposed and susceptible to wear. Joints of the knees and hands are most often affected, as also may be one or more of the spine, hips, ankles and shoulders. In both RA and OA, degeneration of the weight bearing joints such as the hips and knees can be especially debilitating and often requires surgery to relieve pain and increase mobility.
No means currently exist for halting or reversing the degenerative changes brought about by RA and related arthritic disorders. At the same time, approximately 37 million Americans seek symptomatic relief in the form of prescription drugs. In such cases nonsteroidal, anti-inflammatory drugs (NSAIDS) are most often prescribed. While these compounds often alleviate or palliate the arthritic symptoms, they frequently have undesirable side effects, for example, nausea and gastrointestinal ulceration. Other compounds commonly prescribed for the treatment of arthritic disorders are the corticosteroids, such as triamcinolone, prednisolone and hydrocortisone. These drugs also have undesirable side effects, particularly where long term use may be required, and so may be contraindicated in many patients. In addition to difficulties in determining effective dosages, a number of adverse reactions have been reported during intra-articular treatment with these and other steroids. As a result, the use of corticosteroid treatments in the management of arthritic disorders is currently being reassessed.
As an alternative to symptomatic and palliative measures for treating OA and RA as described above, mechanical repair of arthritic joints, when feasible, involves orthopedic surgery to replace worn joints with an artificial prosthesis, or with a biological graft. With more than thirty million Americans suffering from these disabling diseases, such surgery poses enormous medical and economic challenges and is not without its own risks and contraindications.
Osteoarthritis, also known as degenerative joint disease, is one of the most common types of arthritis. It is characterized by the breakdown of the cartilage within a joint, causing painful rubbing of one bone of the joint against another bone and leading to a loss of movement within the affected joint. Osteoarthritis can range from very mild to very severe, and most commonly affects middle-aged and older people. In particular, OA often affects hands and weight-bearing joints such as the knees, hips, feet and back. Although age is a leading risk factor, at present the etiology and pathogenesis of this condition remains largely unknown. Many environmental factors and other independent conditions have been associated with an increased risk for having or developing osteoarthritis, including obesity, previous injury and/or menisectomy (e.g., sports-related injuries or other accidental injury), occupation-related activities that involve repeated knee bending, smoking, sex hormones, gynecological disorders and other metabolic factors. Chondrocalcinosis is another form of degenerative joint disease related to osteoarthritis, in which abnormal calcification occurs in the articular cartilage.
At present accurate diagnosis of osteoarthritis is in general possible only when the disease has progressed significantly. Physicians can do little more than make a diagnosis of osteoarthritis based on a physical examination and a history of symptoms. Examination by X-ray is typically used only to confirm diagnosis. A recent study concluded that weight loss in middle-aged people who are overweight can significantly reduce the risk or even prevent osteoarthritis of the knee from developing. In such cases, improved accuracy in diagnosing an individual's predisposition to developing osteoarthritis would provide distinct advantages.
Accordingly, as provided herein, certain embodiments of the present invention are drawn to compositions and methods for the diagnosis of arthritis and related disorders. In related embodiments, the invention provides compositions and screening methods for compounds that can be used to treat such disorders, preferably using high-throughput screening methods as known in the art or later developed based on the disclosures herein. Such treatment can be remedial, therapeutic, palliative, rehabilitative, preventative, impeditive or prophylactic in nature.
III. Canine Hip Dysplasia and Other Disorders in Non-Human Animals
In certain embodiments the invention relates to compositions and methods for the early diagnosis of dogs affected with canine hip dysplasia. In related embodiments, the invention pertains in part to compositions and methods for the diagnosis of arthritis, dysplasia and related diseases and disorders in other non-human animals.
Canine hip dysplasia is a common orthopedic disease affecting millions of dogs in the United States alone. Canine hip dysplasia affects many breeds of dogs, but is of particular high incidence in the larger breeds. Included in the more than 80 affected canine breeds are German shepherd, Newfoundland, Old English sheepdog, English bulldog, Labrador retriever, other retriever breeds, Irish setter, Great Dane, and St. Bernard. The disease is characterized by laxity and incongruity of the hip joint, which results in degeneration of joint tissues. Osteoarthritis develops as a result of the abnormal positioning of the head of the femur in relation to the joint due to laxity, and results in the erosion of joint cartilage, and inflammation of the synovium. The development in a dog of osteoarthritis in a dysplastic hip joint is a benchmark sign of canine hip dysplasia.
Canine hip dysplasia is believed to be a hereditary disease of complex genetic and environmental bases. Clinical symptoms range from mild hip joint discomfort to severe debilitation, and the disease is the most common cause of lameness in posterior limbs and joints. However, in most cases the clinical symptoms of dysplasia appear in affected dogs late in life and long after initiation of the disease process, which may commence during the first 6 to 12 months of age. Early diagnosis (e.g., at less than one year of age) of canine hip dysplasia is desirable and useful, for example, to permit dog breeders to accurately identify affected dogs at an early age in order to remove affected dogs from breeding programs. Early diagnosis may also permit treatment before disease progression can advance. For example, management of the affected dog's weight through physical activity and diet may be initiated to limit strain on the hip joints. Alternatively, Biocompatible Osteoconductive Polymer (BOP) shelf arthroplasty, a surgical procedure in which a polymer is used to rebuild the defective hips of dysplastic dogs to prevent subluxation, may be elected.
A current method for detecting hip dysplasia, disclosed in U.S. Pat. No. 5,482,055, is based on compression-distraction stress radiography. This method measures joint laxity that is related to the presence or absence of osteoarthritis (Smith et al., 1993 Am. J. Vet. Res. 54:1021–42; Smith et al., 1990 J. Am. Vet. Med. Assoc. 196:59–70). This stress method elicits passive laxity, which is the maximal lateral displacement of the femoral heads that occurs when a force is used to distract the hip joint. An adjustable device, a “distractor”, is used to reveal passive laxity, and to quantify lateral displacement of the femoral head by a measurement called the “distraction index”. This index is used as a measure of passive laxity and as a predictive value, wherein below a certain value it is unlikely that the dog will develop osteoarthritis. For example, in Labrador retrievers, a distraction index of 0.3 is indicative of tight hip joints, and an index of >0.7 is indicative of loose hip joints (passive laxity). Thus, as the distraction index increases from 0.3 to 0.7, the probability of the development of osteoarthritis increases. However, a problem arises in that the outcome for Labradors having a distraction index in this range cannot reliably be predicted (Smith et al., 1993, supra; Lust et al., 1993 Am. J. Vet. Res. 54:1990–9). Likely reasons include the other components of the hip joint structure, such as acetabular and femoral head conformation, which contribute to functional joint stability and prevent the conversion of intermediate degrees of passive laxity into hip subluxation during ambulation.
IV. Mitochondria
As noted above, because metabolic energy production in vertebrate articular chondrocytes is believed to proceed via anaerobic respiration (e.g., glycolytic ATP synthesis), little or no attention has been paid to the relationship between mitochondrial oxidative phosphorylation and arthritic disorders. By way of background, mitochondria are the main energy source in cells of higher organisms, and provide direct and indirect biochemical regulation of a wide array of cellular respiratory, oxidative and metabolic processes. Such processes include electron transport chain (ETC) activity, which drives oxidative phosphorylation to produce metabolic energy in the form of adenosine triphosphate (ATP), and which also underlies a central mitochondrial role in intracellular calcium homeostasis.
Mitochondrial ultrastructural characterization reveals the presence of an outer mitochondrial membrane that serves as an interface between the organelle and the cytosol, a highly folded inner mitochondrial membrane that appears to form attachments to the outer membrane at multiple sites, and an intermembrane space between the two mitochondrial membranes. The subcompartment within the inner mitochondrial membrane is commonly referred to as the mitochondrial matrix. (For a review, see, e.g., Ernster et al., 1981 J. Cell Biol. 91:227s.) The cristae, originally postulated to occur as infoldings of the inner mitochondrial membrane, have recently been characterized using three-dimensional electron tomography as also including tube-like conduits that may form networks, and that can be connected to the inner membrane by open, circular (30 nm diameter) junctions (Perkins et al., 1997, Journal of Structural Biology 119:260). While the outer membrane is freely permeable to ionic and non-ionic solutes having molecular weights less than about ten kilodaltons, the inner mitochondrial membrane exhibits selective and regulated permeability for many small molecules, including certain cations, and is impermeable to large (>˜10 kDa) molecules.
Altered or defective mitochondrial activity, including but not limited to failure at any step of the ETC, may result in catastrophic mitochondrial collapse that has been termed “permeability transition” (PT) or “mitochondrial permeability transition” (MPT). According to generally accepted theories of mitochondrial function, proper ETC respiratory activity requires maintenance of an electrochemical potential (ΔΨm) in the inner mitochondrial membrane by a coupled chemiosmotic mechanism. Altered or defective mitochondrial activity may dissipate this membrane potential, thereby preventing ATP biosynthesis and halting the production of a vital biochemical energy source. In addition, mitochondrial proteins such as cytochrome c or intermembrane space proteins may leak out of the mitochondria after permeability transition and may induce the genetically programmed cell suicide sequence known as apoptosis or programmed cell death (PCD).
Four of the five multi-subunit protein complexes (Complexes I, III, IV and V) that mediate ETC activity are localized to the inner mitochondrial membrane, which is the most protein rich of biological membranes in cells (75% by weight); the remaining ETC complex (Complex II) is situated in the matrix. In at least three distinct chemical reactions known to take place within the ETC, positively-charged protons are moved from the mitochondrial matrix, across the inner membrane, to the intermembrane space. This disequilibrium of charged species creates an electrochemical potential of approximately 220 mV referred to as the “proton motive force” (PMF), which is often represented by the notation Δψ or Δψm and represents the sum of the electric potential and the pH differential across the inner mitochondrial membrane (see, e.g., Ernster et al., 1981 J. Cell Biol. 91:227s and references cited therein).
This membrane potential provides the energy contributed to the phosphate bond created when adenosine diphosphate (ADP) is phosphorylated to yield ATP by ETC Complex V, a process that is “coupled” stoichiometrically with transport of a proton into the matrix; Δψm is also the driving force for the influx of cytosolic Ca2+ into the mitochondrion. Under normal metabolic conditions, the inner membrane is largely impermeable to proton movement from the intermembrane space into the matrix, leaving ETC Complex V as the primary means whereby protons can return to the matrix. When, however, the integrity of the inner mitochondrial membrane is compromised, as occurs during MPT that may accompany a disease associated with altered mitochondrial function, protons are able to bypass the conduit of Complex V without generating ATP, thereby “uncoupling” respiration because electron transfer and associated proton pumping yields no ATP. Thus, mitochondrial permeability transition involves the opening of a mitochondrial membrane “pore”, a process by which, inter alia, the ETC and Δψmare uncoupled, Δψm collapses and mitochondrial membranes lose the ability to selectively regulate permeability to solutes both small (e.g., ionic Ca2+, Na+, K+, H+) and large (e.g., proteins).
The mitochondrial permeability transition “pore” may not be a discrete assembly or multi-subunit complex, and the term thus refers instead to any mitochondrial molecular component (including, e.g., a mitochondrial membrane per se) that regulates the inner membrane selective permeability where such regulated function is impaired during MPT. A mitochondrial molecular component may be a protein, polypeptide, peptide, amino acid or derivative thereof; a lipid, fatty acid or the like, or derivative thereof; a carbohydrate, saccharide or the like or derivative thereof; a nucleic acid, nucleotide, nucleoside, purine, pyrimidine or related molecule, or derivative thereof, or the like; or any other biological molecule that is a constituent of a mitochondrion. A mitochondrial pore component may be any mitochondrial molecular component that regulates the selective permeability characteristic of mitochondrial membranes as described above, including those responsible for establishing ΔΨm and those that are functionally modified during MPT.
Without wishing to be bound by theory, it is unresolved whether this pore is a physically discrete conduit that is formed in mitochondrial membranes, for example by assembly or aggregation of particular mitochondrial and/or cytosolic proteins and possibly other molecular species, or whether the opening of the “pore” may simply represent a general increase in the porosity of the mitochondrial membrane. In any event, certain mitochondrial molecular components may contribute to the MPT mechanism, including ETC components or other mitochondrial components described herein. For example, some non-limiting examples of mitochondrial or mitochondria associated proteins that appear to contribute to the MPT mechanism include members of the voltage dependent anion channel (VDAC, also known as porin) family of proteins, the mitochondrial calcium uniporter, mitochondria associated hexokinase(s), peripheral benzodiazepine receptor, and intermembrane creatine kinases.
MPT may result from direct or indirect effects of mitochondrial genes, gene products or downstream mediator molecules and/or extramitochondrial genes, gene products or downstream mediators. MPT may also result from other known or unknown causes. Loss of mitochondrial potential may be a critical event in the progression of diseases associated with altered mitochondrial function, including degenerative diseases.
Mitochondrial defects may contribute significantly to the pathogenesis of diseases associated with altered mitochondrial function. Such defects may be related to the discrete mitochondrial genome that resides in mitochondrial DNA and/or to the extramitochondrial genome, which includes nuclear chromosomal DNA and other extramitochondrial DNA, For example, alterations in the structural and/or functional properties of mitochondrial components, including alterations deriving from genetic and/or environmental factors or alterations derived from cellular compensatory mechanisms, may play a role in the pathogenesis of any disease associated with altered mitochondrial function.
A number of degenerative diseases are thought to be caused by, or to be associated with, alterations (e.g., increases or decreases) in mitochondrial function. Without wishing to be bound by theory, such alterations may be global, manifesting themselves in virtually all cell and tissue types in an affected individual, or they may be more apparent in specific cell or tissue types that appear particularly relevant to a given disease. Diseases associated with altered mitochondrial function include disorders that are accompanied by neurodegeneration (e.g., Alzheimer's Disease (AD); Parkinson's Disease; Huntington's disease; dystonia; Leber's hereditary optic neuropathy; schizophrenia; mitochondrial encephalopathy, lactic acidosis, and stroke (MELAS); and myoclonic epilepsy, ragged red fiber syndrome (MERRF), cancer) as well as disorders in which degeneration of other specialized tissues may be present (e.g., psoriasis; hyperproliferative disorders; mitochondrial diabetes and deafness (MIDD); and diabetes mellitus. The extensive list of additional diseases associated with altered mitochondrial function continues to expand as aberrant mitochondrial or mitonuclear activities are implicated in particular disease processes.
A hallmark pathology of AD and potentially other diseases associated with altered mitochondrial function is the death of selected cellular populations in particular affected tissues, which results from apoptosis (also referred to as “programmed cell death” or PCD). Mitochondrial dysfunction is thought to be critical in the cascade of events leading to apoptosis in various cell types (Kroemer et al., FASEB J. 9:1277–87, 1995). Altered mitochondrial physiology may be among the earliest events in PCD (Zamzami et al., J. Exp. Med. 182:367–77, 1995; Zamzami et al., J. Exp. Med. 181:1661–72, 1995) and elevated reactive oxygen species (ROS) levels that result from such altered mitochondrial function may initiate the apoptotic cascade (Ausserer et al., Mol. Cell. Biol. 14:5032–42, 1994).
Thus, in addition to their role in energy production in growing cells, mitochondria (or, at least, mitochondrial components) participate in apoptosis (Newmeyer et al., 1994, Cell 79:353–364; Liu et al., 1996, Cell 86:147–157). Apoptosis is apparently also required for, inter alia, normal development of specialized tissues (e.g., ablation of obsolete cells during developmentally programmed tissue remodeling) and proper functioning of the immune system. Moreover, some disease states are thought to be associated with either insufficient (e.g., cancer, autoimmune diseases) or excessive (e.g., stroke damage, AD-associated neurodegeneration) levels of apoptosis. For general reviews of apoptosis, and the role of mitochondria therein, see Green and Reed (1998, Science 281:1309–1312), Green (1998, Cell 94:695–698) and Kromer (1997, Nature Medicine 3:614–620). Hence, agents that affect apoptotic events, including those associated with mitochondrial components, might have a variety of palliative, prophylactic and therapeutic uses.
From the foregoing, it is clear that none of the current pharmacological therapies corrects the underlying biochemical defect in arthritic disorders such as RA and OA. Neither do any of these currently available treatments improve all of the physiological abnormalities in arthritic disorders such as abnormal articular chondrocyte activity, cartilage degradation, articular erosion and severe joint deformity. In addition, treatment failures are common with these agents, such that multi-drug therapy is frequently necessary.
Clearly there is a need for improved diagnostic methods for early detection of a risk for developing an arthritic disorder, and for better therapeutics that are targeted to correct biochemical and/or metabolic defects responsible for this disease, regardless of whether such a defect underlying altered mitochondrial function may have mitochondrial or extramitochondrial origins. The present invention provides compositions and methods related to indicators of altered mitochondrial function that are useful for determining the risk and degree of progression of an arthritic disorder and for treating this disease, and offers other related advantages.